Selective Antagonism of Opioid-Induced Ventilatory Depression by an Ampakine Molecule in Humans Without Loss of Opioid Analgesia

Oertel, B.; Felden, Lisa; Trân, Pierre V.; Bradshaw, Mark; Angst, Martin S.; Schmidt, Helmut; Johnson, Steven A.; Greer, John J.; Geißlinger, Gerd; Varney, Mark A.; Lötsch, Jörn

doi:10.1038/clpt.2009.194

Cited by 111 publications

(108 citation statements)

References 31 publications

(45 reference statements)

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Section: Ampakines and Their Use In Treating Hypoventilationmentioning

confidence: 99%

“…The ampakine used in this study, CX717, is metabolically stable, clinically safe, and effectively crosses the blood-brain barrier (11,14,47,48). CX717 has been used in both animal models (15,17,20) and clinical trials to alleviate respiratory depression due to opioids (14). CX717 does not directly antagonize opioid receptors, because, in both rats and humans, CX717 counteracts respiratory depression without influencing analgesia (15)(16)(17)20).…”

Section: Ampakines and Their Use In Treating Hypoventilationmentioning

confidence: 99%

“…These drugs successfully stimulated breathing after opiate-induced respiratory depression in clinical trials (13,14). Importantly, preclinical studies show that ampakines most effectively stimulate breathing when the neural input to respiratory muscles is blunted (13,(15)(16)(17).…”

mentioning

confidence: 99%

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Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines

ElMallah

Pagliardini

Turner

et al. 2015

Am J Respir Cell Mol Biol

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Pompe disease results from a mutation in the acid a-glucosidase gene leading to lysosomal glycogen accumulation. Respiratory insufficiency is common, and the current U.S. Food and Drug Administration-approved treatment, enzyme replacement, has limited effectiveness. Ampakines are drugs that enhance a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor responses and can increase respiratory motor drive. Recent work indicates that respiratory motor drive can be blunted in Pompe disease, and thus pharmacologic stimulation of breathing may be beneficial. Using a murine Pompe model with the most severe clinical genotype (the Gaa 2/2 mouse), our primary objective was to test the hypothesis that ampakines can stimulate respiratory motor output and increase ventilation. Our second objective was to confirm that neuropathology was present in Pompe mouse medullary respiratory control neurons.The impact of ampakine CX717 on breathing was determined via phrenic and hypoglossal nerve recordings in anesthetized mice and whole-body plethysmography in unanesthetized mice. The medulla was examined using standard histological methods coupled with immunochemical markers of respiratory control neurons. Ampakine CX717 robustly increased phrenic and hypoglossal inspiratory bursting and reduced respiratory cycle variability in anesthetized Pompe mice, and it increased inspiratory tidal volume in unanesthetized Pompe mice. CX717 did not significantly alter these variables in wild-type mice. Medullary respiratory neurons showed extensive histopathology in Pompe mice. Ampakines stimulate respiratory neuromotor output and ventilation in Pompe mice, and therefore they have potential as an adjunctive therapy in Pompe disease.

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Section: Ampakines and Their Use In Treating Hypoventilationmentioning

confidence: 99%

Section: Ampakines and Their Use In Treating Hypoventilationmentioning

confidence: 99%

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Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines

ElMallah

Pagliardini

Turner

et al. 2015

Am J Respir Cell Mol Biol

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“…Whilst respiratory depression can be effectively treated by the opioid antagonists naloxone and naltrexone, analgesic efficacy is also reduced. Agents such as the a-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptor agonists (ampakines) and minocycline have been shown to suppress opioid-induced respiratory depression without affecting analgesic efficacy 81,82 . Serotonin (5-hydroxy tryptamine,5-HT) agonists, by virtue of the role of 5-HT neurones in the maintenance of respiratory drive, have also been evaluated for the suppression of opioid-induced respiratory depression, but not found to be effective 82 .…”

Section: Novel Molecular Developmentsmentioning

confidence: 99%

Opioids: a two-faced Janus

Ahlbeck

2011

Current Medical Research and Opinion

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Background: Long-term pain is a debilitating condition that is costly to treat and has a significant impact on patient quality of life. Classical opioids have been used for the treatment of pain for centuries and are one of the most effective drug classes available for acute severe pain and long-term pain. However, concerns regarding adverse effects, tolerance to analgesic effects and the potential for addiction have resulted in a reluctance to prescribe and use opioids for the management of long-term non-cancer pain. Adverse events, including gastrointestinal side effects such as constipation, nausea and vomiting, and central nervous system side effects such as sedation are responsible for as many as one in five patients discontinuing opioid treatment, often leading to inadequate pain relief and poor patient quality of life. Therefore, new analgesic therapies are needed that are associated with fewer adverse effects, whilst providing sustainable pain relief for patients with long-term pain.

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“…A depressão respiratória é um dos efeitos mais temidos durante o uso dos opioides (OERTEL et al, 2009) (GOZZANI, 1994). Em geral, a sedação, após uso de opioides, é vista como um problema, comumente, no início da terapia.…”

Section: Depressão Respiratóriaunclassified

Comparação dos efeitos do sufentanil e da clonidina administrados por via endovenosa para sedação em pacientes submetidos a cateterismo cardíaco

Rocha¹

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A A A Aquele que possui a sinceridade não se limita a quele que possui a sinceridade não se limita a quele que possui a sinceridade não se limita a quele que possui a sinceridade não se limita a realizar a perfeição de si mesmo. Com essa realizar a perfeição de si mesmo. Com essa realizar a perfeição de si mesmo. Com essa realizar a perfeição de si mesmo. Com essa qualidade completa também os outros homens e qualidade completa também os outros homens e qualidade completa também os outros homens e qualidade completa também os outros homens e coisas. O completar coisas. O completar coisas. O completar coisas. O completar----se a si mesmo mostra a sua se a si mesmo mostra a sua se a si mesmo mostra a sua se a si mesmo mostra a sua perfeita virtude. O completar aos outros homens e perfeita virtude. O completar aos outros homens e perfeita virtude. O completar aos outros homens e perfeita virtude. O completar aos outros homens e coisas m coisas m coisas m coisas mostra o seu conhecimento. Estas são duas ostra o seu conhecimento. Estas são duas ostra o seu conhecimento. Estas são duas ostra o seu conhecimento. Estas são duas virtudes que correspondem à natureza, este o modo virtudes que correspondem à natureza, este o modo virtudes que correspondem à natureza, este o modo virtudes que correspondem à natureza, este o modo pelo qual se efetua uma união no exterior e no pelo qual se efetua uma união no exterior e no pelo qual se efetua uma união no exterior e no pelo qual se efetua uma união no exterior e no interior. AGRADECIMENTOSA realização deste trabalho só foi possível graças a colaboração direta ou indireta de muitas pessoas. Manifesto a todas elas a minha gratidão e, em particular:• aos meus irmãos, Antonio Miranda Rocha Júnior, Anício MarcelCarvalho Rocha e Aparecida Gabriela Carvalho Rocha, que me ensinaram a compartilhar e a dividir todas as minhas conquistas;• aos meus mestres que confiaram em mim e me incentivaram a buscar o melhor, particularmente ao Prof. Lino Lemônica e ao amigo Jedson da Silva Nascimento;• a todos os amigos e funcionários do Hospital Santa Izabel que ajudaram na realização deste trabalho, principalmente a equipe da hemodinâmica;• aos amigos do Grupo de Anestesiologia do Hospital Santa Izabel, pela compreensão e auxílio nos momentos que precisei me ausentar das minhas atividades profissionais em Salvador para a realização deste trabalho;• à amiga Lilian Mendes de Vasconcelos pela amizade e por todo o tempo que esteve envolvida na realização desta pesquisa;• aos funcionários da secretaria e do serviço de computação do Introdução e Literatu Introdução e Literatu Introdução e Literatu Introdução e Literatura ra ra ra 10 10 10 10 LISTA DE FIGURAS ABSTRACTBackground and objectives -Sedation for cardiac catheterization, although

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Selective Antagonism of Opioid-Induced Ventilatory Depression by an Ampakine Molecule in Humans Without Loss of Opioid Analgesia

Cited by 111 publications

References 31 publications

Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines

Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines

Opioids: a two-faced Janus

Comparação dos efeitos do sufentanil e da clonidina administrados por via endovenosa para sedação em pacientes submetidos a cateterismo cardíaco

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